Mass spectrometry is widely used in analytical chemistry and other fields for identifying unknown compounds, screening for the presence of certain target compounds, identifying the products of chemical reactions, studying the kinetics or mechanisms of chemical reactions, etc. Since mass spectrometers are capable of directly detecting only ions, provision must be made for ionizing the molecular constituents of samples to be analyzed. Many different types of ion sources are available for this purpose.
In electron ionization (EI) ion sources, the electrons emitted from a thermionic filament are caused to directly impinge upon gaseous molecules of one or more chemical constituents of a sample under investigation. These chemical constituents may include one or more analyte compounds or matrix compounds derived from the sample. The interaction of energetic electrons of the electron beam with an electron cloud of a neutral molecule may effectively “dislodge” one or more electrons of the neutral molecule and may additionally cleave chemical bonds. This combination of ionization and fragmentation may lead to the formation of one or more cation species. These cation species are analyzed by a mass analyzer. Such electron ionization sources are commonly employed in gas chromatography/mass spectrometry (GCMS) instruments.
FIG. 1 is a symbolic diagram of an ion source 1 configured to produce analyte ions by electron ionization (EI). Ion source 1 includes an ionization volume 2 into which sample molecules including analyte molecules are introduced via, for example, an end portion of a gas chromatograph (GC) column 3. The GC column 3 may be a fused silica capillary tube of a type well known in the art. Ionization volume 2 is located inside a vacuum chamber evacuated to a suitable pressure by a not-illustrated pumping system. A stream of electrons is generated by passing an electric current provided by a filament electric current source 9 through thermionic filament 4. The filament current source 9 is located externally to the vacuum chamber and electrically connected to the filament 4 via a vacuum feed-through (not shown). Filament 4 is typically fabricated from a refractory metal such as rhenium (or alloys thereof). The refractory metal may include a low work function coating such as thorium oxide or yttrium oxide. Electrons emitted by filament 4 travel, under the influence of an electrical field established by applying suitable potentials to the filament 4 and electrodes 6, through aperture 5 into the ionization volume 2 interior. The electron beam may also be guided by a magnetic field established by magnets (not shown) located behind and on the opposite side of ionization volume 2 from filament 4. The electrons interact with the sample molecules within ionization volume 2 to form sample ions. The sample ions are extracted from ionization volume 2 via ion exit aperture 7 by ion lenses 8, and are transported through an ion guide or other suitable ion optics to a mass analyzer for analysis.
Unfortunately, the ionization efficiency of EI is restricted to a maximum of about 0.01% due to the electron beam current density being limited by space charge. If the electrons are given a kinetic energy in the range of 50-100 eV, the de Broglie wavelength of the electron is about the same as a chemical bond length and energy transfer is maximized. Greater electron energy does not improve efficiency. If the imparted kinetic energy is greater than 100 eV, then the de Broglie wavelength is smaller than bond lengths and the molecules become transparent to the electrons. Electron ionization is often considered to be a “hard” ionization technique, causing extensive ion fragmentation. This property is detrimental for use of EI in conjunction with analyses that make use of selected-reaction-monitoring (for example, analyses of proteins and other biological molecules) in which accurate analysis depends on experimental control of the degree of ion fragmentation.
In contrast to EI, photoionization techniques are often considered to be “soft” ionization techniques, generating a higher proportion of molecular ions or ions formed by protonation of a molecule and creating fewer fragment ions than the EI technique. For example, the technique of single-photon ionization makes use of absorption, by each molecule, of an individual photon comprising sufficient energy to expel a valence electron from the molecule. Because it is mechanistically the simplest of the photoionization techniques, single-photon ionization is extensively employed in most conventional Atmospheric Pressure Photo-Ionization (APPI) ion sources. Typical ionization energies are such that either ultraviolet (UV) radiation sources emitting in the 150-320 nm range or vacuum-ultraviolet (VUV) radiation sources that emit wavelengths of 150 nm and shorter are generally required. Typical APPI ion sources may comprise a UV-emitting lamp or a VUV-emitting laser, such as an excimer laser, that illuminates a vaporized sample (e.g. an effluent from a gas chromatograph or a gas produced by evaporation of a liquid sample) with UV or VUV light. Although single-photon ionization is used extensively in APPI ion sources in the mass spectrometric study of a variety of analytes, it has some disadvantages as a general mass spectrometric ionization technique. Foremost among these is that the collision between a photon and an individual molecule is a statistically improbable process. Secondly, UV wavelengths and the shorter VUV wavelengths are strongly absorbed by common optical materials. For example, the optical transmission curves of borosilicate and soda-lime glasses decrease rapidly at wavelengths shorter than about 400 nm and even that of “UV glass” decreases rapidly at wavelengths shorter than about 250 nm—as well as by gaseous nitrogen. These difficulties can be overcome, in part, by proper choice of optical materials, by ionization in high vacuum and by providing high-photon-flux emitters. Nonetheless, present limitations cause the ionization efficiency of APPI to be significantly less than that of EI.
Multi-photon ionization techniques make use of the near-simultaneous absorption of more than one photon by an individual molecule, such that the combined absorbed energies exceed the ionization potential of the molecule. In such techniques, which include Resonance-Enhanced Multiphoton Ionization (REMPI), a first photon absorption event creates an electronically excited intermediate state. This is then followed, prior to the decay of the excited state, by another photon absorption event that causes ionization of the molecule. Because the near simultaneous absorption of two photons by a molecule is even more improbable than the absorption of a single photon, a very high photon flux is required.
Strong field photo-ionization (SFPI) is another photoionization technique that utilizes the electric field generated by an intense laser pulse to remove electrons from the gas chromatograph (GC) column effluent. The SFPI approach is both “softer” than traditional electron ionization (EI), thereby resulting in increased molecular ion formation, as well as more efficient than EI and single-photon and multi-photon techniques. Specifically, the SFPI method has been demonstrated to produce 100% ionization efficiency, at sufficient laser powers, for molecules inside the laser pulse's electric field as compared to, at best, 0.01% efficiency for electron ionization and presently-best-achievable 0.1% efficiency for single-photon absorption. Moreover, UV wavelengths are not required for SFPI, since absorption of photons by molecules is not required. Instead, ionization is caused by a large spatial electric field gradient produced by the simultaneous introduction of a large quantity of coherent photons. As a result, the SFPI technique can make use of pulsed light of any nominal emission wavelength.
The mechanism by which the SFPI technique generates ions is thought to be related to the mechanism of generation of UV light by High Harmonic Generation (HHG). The set of drawings shown in FIGS. 2A-2D illustrate the mechanism by which UV light is generated, according to the theory of HHG. The mechanistic steps illustrated in the first two drawings (FIGS. 2A-2B) are believed to also apply to ionization as observed in SFPI. FIG. 2A schematically shows the fundamental state of a valence electron 75a (denoted e−) of an atom in a gas in the absence of a perturbing electric field. In this drawing, curve 74a schematically represents the potential energy of the electron versus distance away from the position of its valence shell. Residence within the valence shell represents a state of minimum potential energy for the valence electron. Horizontal line 72a schematically represents the potential energy of the hypothetical free electron 75b, fully liberated from the atom. Thus, the vertical distance between the electron 75a in the valence shell and the hypothetical free electron 75b represents the normal ionization potential of the atom.
In the presence of a strong electrical field gradient (dE/dx) as produced by the passage of a high-energy laser pulse, both the electrical potential energy in free space 72b and the potential energy associated with bound electronic displacement 74b may be sufficiently perturbed (dE) on the spatial scale of an atom (dx) such that the electron may quantum-mechanically tunnel from its valence position 75a to a free state 75c without a gain in potential energy. When the electric field reverses, one-half cycle later (FIG. 2C), the now-displaced electron is pumped to a higher energy state relative to the energy of the valence shell as the slope of the electrical potential in free space 72c and of the electrical potential of the non-free electron 74c change. The electric-field reversal enables the high-potential energy free electron 75d to fall back into the valence shell so as to once again become a bound electron 75e with the liberation of a UV photon 77.
In the SFPI technique, the above-described process is interrupted after the second step (i.e., as shown in FIG. 2B) by application of a superimposed secondary electric field that causes sufficient physical separation of the free electron 75c from the simultaneously-generated cation such that recombination does not occur. The superimposed secondary electric field is generated by high voltage applied to electrodes that are disposed in the vicinity of the path of the light pulse. The application of high voltage to such electrodes may be synchronized to the passage of the light pulses through the gas being ionized.
Conveniently, the SFPI technique can conveniently make use of conventional titanium-doped sapphire (Ti:sapphire) pulsed lasers that emit in the infrared (IR) or near-infrared (NIR) range of 650 to 1100 nm. Light within this wavelength range is much easier to generate and direct than is light of UV wavelengths. Further, photons within this IR to NIR wavelength range are of lower energy (individually) than photons of UV-visible wavelengths, thus rendering as less likely the competing ionization mechanism of multi-photon ionization. Accordingly, less ion fragmentation and a greater proportion of molecular ions or protonated molecules (cations) are expected using such IR-NIR wavelengths. The Ti:sapphire lasing medium is usually pumped with a pump laser that emits green light, such as an argon-ion laser or a frequency doubled Nd:YAG laser.
FIG. 3 is a schematic depiction of a known mass spectrometer ionization source 50, as taught in international (PCT) application publication WO 2013/098610 A1, that may employ the principle of strong-field ionization using a pulsed laser. The ionization source 50 can comprise an ionization chamber 12 for receiving an analyte of interest so as to expose the analyte to short laser pulses suitable for ionizing the analyte. The ionization chamber 12 can be connected to a mass spectrometer 14 (shown only partially) via an aperture 16 of a sampling cone 18 through which ions generated in the ionization chamber can pass to enter the spectrometer. The mass spectrometer can comprise one or more quadrupole ion guides and analyzers, such as the illustrated ion guide Q0 that focuses and guides the ions entering through the aperture of the sampling cone to other stages of the mass spectrometer (not shown).
Still with reference to FIG. 3, the ionization chamber can comprise an annular metal holder 20 that is coupled to an electrically insulating section 22. The electrically insulating section 22 can comprise any of a variety of materials, including without limitation, ceramic, glass, or plastic. A channel 24 extends through the metal holder 20 into the ionization chamber 12 to provide a passageway for delivery of an analyte, which can be in a gaseous state, into the ionization chamber 12, e.g., via a buffer gas, such as helium. The sample can be the output of a gas chromatograph, a liquid chromatograph, or other source 25. Another channel 26 extends through the insulating section 22 into the ionization chamber to provide a passageway for delivery of a carrier gas into the ionization chamber to carry the generated ions to the aperture 16 of the sampling cone 18.
Still with reference to FIG. 3, a radiation-transmissive optical window 28 is coupled to the metal holder 20 and allows the passage of ionizing radiation 30 from an external radiation source 32 into the ionization chamber 12. The material from which the optical window 28 is formed can be selected based on the wavelength of the ionizing radiation 30 to allow the passage of that radiation into the chamber 12. A variety of radiation sources providing ionizing radiation can be employed. The radiation source 32 may provide short laser pulses, e.g., pulses having a pulse width in a range of about 2 femtoseconds to about 1 picosecond and may comprise, for example, a Ti:Sapphire laser configured to provide femtosecond pulses, e.g., pulses having a pulse width in range of about 2 fs to about 100 fs or a fiber laser configured to provide femtosecond pulses.
Still with reference to FIG. 3, a dichroic mirror 34 receives the radiation pulses generated by the radiation source 32 and reflects the radiation pulses onto a focusing objective 36 that in turn focuses the radiation pulses into a focal volume 38 (also referred to as the ionization volume) within the ionization chamber 12. A camera 40 can be positioned behind the dichroic mirror 34 to allow viewing the ionization chamber.
The SFPI method requires the provision of a light power density on the order of 1014 W/cm2 (e.g., K Codling, L J Frasinki, Dissociative ionization of small molecules in intense laser fields, J. Phys. B: At. Mol. Opt. Phys. 26 (1993), pp. 783-809). Such power density may be achieved, with currently available lasers, in the vicinity of the focal region (beam waist from 10-100 μm) of a laser pulse of short duration (less than or equal to 150 fs). It has been shown that 100% of molecules within such a region may be ionized under such circumstances. Unfortunately, sample effluent streams (e.g., as introduced from a gas chromatograph column) are generally much larger than the size of the required focal region. For example, conventional GC columns emit an effluent plume from the entire cross section of a conventional lumen of 250 μm diameter. The diameter of the plume will generally expand after exiting the column. Thus, the ionization zone of any individual pulse comprises only a very small proportion of the analyte plume. The size of the ionization zone can be increased by reducing the pulse repetition rate of a laser so as to achieve greater energy per pulse without an increase in average laser power output. However, doing so causes a significant proportion of the total volume of an effluent plume to flow through the spatial profile of the zone at times when the laser is not emitting light.